Reduced phagocytic activity of polymorphonuclear leukocytes in alpha(1,3) fucosyltransferase VII-deficient mice.

Deficiencies in adhesion molecules or their counter-receptors in humans may have severe consequences as exemplified by leukocyte adhesion deficiency (LAD) I or II syndromes. Because such diseases occur with great rarity, animal models are valuable for studying the role of particular adhesion molecules and their natural ligands in immunity. We studied selected immune parameters and general health in mice with a defect in the sialyl-Lewis X antigen (selectin ligand) caused by disruption of the gene encoding alpha(1,3)fucosyltransferase VII (Fuc-TVII). Leukocytes from Fuc-TVII -/- and control mice were tested for adherence to cellophane membranes or polymer particles in vivo and phagocytic activity in vitro. While no difference in adherence was found, the number of neutrophil granulocytes in exudate induced by intraperitoneal injection of polymer beads was reduced in knock-out mice. Moreover, the phagocytic activity in Fuc-TVII -/- mice was significantly reduced. These animals have splenomegaly due to increased hematopoiesis and reduced weight but do not exhibit clinical signs of immunodeficiency. In conclusion, the lack of Fuc-TVII activity leads to several morphological and functional abnormalities without an impact on survival rate.

[Metabolic complications and neurologic manifestations of vitamin B12 deficiency in children of vegetarian mothers]. / Metabolické komplikace a neurologické projevy pri deficitu vitaminu B12 u detí vegetariánských matek.

BACKGROUND: Serious hematological, metabolic and neurological complications owing to the nutritional deficiency of vitamin B12 may occur in infants of mothers on a strict vegetarian diet. METHODS AND RESULTS: The mother of the first child was a strict vegetarian. She had an elevated urinary methylmalonic acid level and a low concentration of serum vitamin B12. Her 13-month-old daughter was exclusively breast-fed until the age of 9 month and then she was fed only vegetables. Physical examination revealed psychomotoric retardation, apathy, muscular hypotonia, abnormal movements and failure to thrive. Laboratory analysis showed a megaloblastic anaemia, a low level of vitamin B12 and methylmalonic aciduria. MRI of the brain revealed diffuse frontotemporoparietal atrophy and retardation of myelination. After treatment with vitamin B12 supplements, abnormal movements disappeared and development improved, but a mild generalised hypotonia continued. A cranial MRI 9 months after treatment still showed signs of retardation of myelination. The second patient, an 8 month-old male, son of a strict vegetarian mother too, was referred for investigation of psychomotoric retardation, hypotonia, dyskinesia, failure to thrive and microcephaly. He was breast-fed and from 6 month of age he had also received fruit juices. Laboratory analysis revealed megaloblastic anaemia, high methylmalonic aciduria and homocystinuria. The patient's and his mother's serum level of vitamin B12 were low. After treatment with vitamin B12 supplements, biochemical and metabolic markers of disease were normal but there continued a generalised hypotonia, microcephaly and language delay. CONCLUSION: Our observations emphasize the health complications of nutritional cobalamine deficiency and a requirement of clinical, biochemical and metabolic monitoring in infants within strict vegetarian families.

A low affinity TCR ligand restores positive selection of CD8+ T cells in vivo.

The T cell repertoire is shaped by the processes of positive and negative selection. During development, the TCR binds self peptide-MHC complexes in the thymus, and the kinetics of this interaction are thought to determine the thymocyte's fate. For development of CD8(+) T cells, the data supporting such a model have been obtained using fetal thymic organ culture. To confirm the fidelity of this model in vivo, we studied development of OT-I TCR-transgenic mice that expressed different individual K(b) binding peptides in thymic epithelial cells under the control of the human keratin 14 promoter. We used a system that allowed TAP-independent expression of the peptide-MHC complex, such that the ability of given peptides to restore positive selection in TAP(o) mice could be assessed. We found that transgenic expression of a TCR antagonist peptide (E1) in vivo efficiently restored positive selection of OT-I T cells in TAP(o) mice. An unrelated transgenic peptide (SIY) did not restore selection of OT-I T cells, nor did the E1-transgenic peptide restore selection of an unrelated receptor (2C), showing that positive selection is peptide specific in vivo, as observed in organ cultures. Neither E1 nor SIY transgenes increased the polyclonal CD8 T cell repertoire size in non-TCR-transgenic animals, arguing that single class I binding peptides do not detectably affect the size of the CD8 T cell repertoire when expressed at low levels. We also observed that OT-I T cells selected in TAP(o)-E1 mice were functional in their response to Ag; however, there was a lag in this response, suggesting that the affinity of the TCR interaction with MHC-self peptide can result in fine-tuning of the T cell response.